The object of the invention was to find novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The present invention relates to benzonitrile compounds which are capable of inhibiting one or more kinases. The compounds are used in the treatment of a multiplicity of disorders, including cancer, septic shock, primary open angle glaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, retinopathy, osteoarthritis, endometriosis, chronic inflammation and/or neurodegenerative diseases, such as Alzheimer's disease.
The present invention relates to compounds and to the use of compounds in which the inhibition, regulation and/or modulation of signal transduction by receptor kinases plays a role, furthermore to pharmaceutical compositions which comprise these compounds and to the use of the compounds for the treatment of kinase-induced diseases.
Since protein kinases regulate virtually every cellular process, including metabolism, cell proliferation, cell differentiation and cell survival, they are attractive targets for therapeutic intervention in the case of various conditions. For example, cell-cycle control and angiogenesis, in which protein kinases play a key role, are cell processes associated with numerous conditions, such as, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular degeneration, diabetes, obesity and pain.
In particular, the present invention relates to compounds and to the use of compounds in which the inhibition, regulation and/or modulation of signal transduction by TBK1 and IKKε plays a role.
One of the principal mechanisms by which cell regulation is effected is through the transduction of extracellular signals across the membrane, which in turn modulate biochemical pathways in the cell. Protein phosphorylation represents one process by which intracellular signals are propagated from molecule to molecule, finally resulting in a cell response. These signal transduction cascades are highly regulated and often overlap, as is evident from the existence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly at serine, threonine or tyrosine residues, and protein kinases have therefore been classified by their specificity of phosphorylation site, i.e. serine/threonine kinases and tyrosine kinases. Since phosphorylation is such a widespread process in cells and since cell phenotypes are mostly influenced by the activity of these pathways, it is currently thought that a number of conditions and/or diseases are attributable to either aberrant activation or functional mutations in the molecular components of kinase cascades. Consequently, considerable attention has been paid to the characterisation of these proteins and compounds which are able to modulate their activity (review articles see: Weinstein-Oppenheimer et al. Pharma. &. Therap., 2000, 88, 229-279).
IKKε and TBK1 are serine/threonine kinases which are highly homologous to one another and to other IkB kinases. The two kinases play an integral role in the innate immune system. Double-stranded RNA viruses are recognised by the Toll-like receptors 3 and 4, and the RNA helicases RIG-I and MDA-5 and result in activation of the TRIF-TBK1/IKKε-IRF3 signalling cascade, which results in a type I interferon response.
In 2007, Boehm et al. described IKKε as a novel breast cancer oncogene [J. S. Boehm et al., Cell 129, 1065-1079, 2007]. 354 kinases were investigated with respect to their ability to recapitulate the Ras-transforming phenotype together with an activated form of the MAPK kinase Mek. IKKε was identified here as a cooperative oncogene. In addition, the authors were able to show that IKKε is amplified and overexpressed in numerous breast cancer cell lines and tumour samples. The reduction in gene expression by means of RNA interference in breast cancer cells induces apoptosis and impairs the proliferation thereof. Eddy et al. obtained similar findings in 2005, which underlines the importance of IKKε in breast cancer diseases [S. F. Eddy et al., Cancer Res. 2005; 65 (24), 11375-11383].
A protumorigenic effect of TBK1 was reported for the first time in 2006. In a screening of a 251,000 cDNA gene library, Korherr et al. identified precisely three genes, TRIF, TBK1 and IRF3, that are typically involved in the innate immune defence as proangiogenic factors [C. Korherr et al., PNAS, 103, 4240-4245, 2006]. In 2006, Chien et al. [Y. Chien et al., Cell 127, 157-170, 2006] published that TBK1−/− cells can only be transformed to a limited extent using oncogenic Ras, which suggests an involvement of TBK1 in the Ras-mediated transformation. Furthermore, they were able to show that an RNAi-mediated knockdown of TBK1 triggers apoptosis in MCF-7 and Panc-1 cells. Barbie et al. recently published that TBK1 is of essential importance in numerous cancer cell lines with mutated K-Ras, which suggests that TBK1 intervention could be of therapeutic importance in corresponding tumours [D. A. Barbie et al., Nature Letters 1-5, 2009].
Diseases caused by protein kinases are characterised by anomalous activity or hyperactivity of such protein kinases. Anomalous activity relates to either: (1) expression in cells which do not usually express these protein kinases; (2) increased kinase expression, which results in undesired cell proliferation, such as cancer; (3) increased kinase activity, which results in undesired cell proliferation, such as cancer, and/or in hyperactivity of the corresponding protein kinases. Hyperactivity relates either to amplification of the gene which encodes for a certain protein kinase or the generation of an activity level which can be correlated with a cell proliferation disease (i.e. the severity of one or more symptoms of the cell proliferation disease increases with increasing kinase level) the bioavailability of a protein kinase may also be influenced by the presence or absence of a set of binding proteins of this kinase.
IKKε and TBK1 are highly homologous Ser/Thr kinases which play a crucial role in the innate immune response through induction of type 1 interferons and other cytokines. These kinases are stimulated in response to viral/bacterial infection. Immune response to viral and bacterial infections involves the binding of antigens, such as bacterial lipopolysaccharide (LPS), viral double-stranded RNA (dsRNA), to Toll-like receptors, subsequent activation of the TBK1 pathway. Activated TBK1 and IKKε phosphorylate IRF3 and IRF7, which triggers the dimerisation and nuclear translocation of these interferon-regulating transcription factors, ultimately inducing a signalling cascade leading to IFN production.
Recently, IKKε and TBK1 have also been implicated in cancer. It has been shown that IKKε cooperates with activated MEK to transform human cells. In addition, IKKε is frequently amplified/overexpressed in breast cancer cell lines and tumours originating from patients. TBK1 is induced under hypoxic conditions and expressed at significant levels in many solid tumours. Furthermore, TBK1 is necessary to support oncogenic Ras transformation, and TBK1 kinase activity is increased in transformed cells and is necessary for their survival in culture. It has likewise been found that TBK1 and NF-kB signalling are essential in KRAS-mutated tumours. TBK1 has been identified as a synthetic lethal partner of oncogenic KRAS.
Lit.:
    Y.-H. Ou et al., Molecular Cell 41, 458-470, 2011;    D. A. Barbie et al., Nature, 1-5, 2009.
WO 2011/046970 A1 describes the use of TBK1 and/or IKKε inhibitors for the treatment of various diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjörgren's syndrome, Aicardi-Goutières syndrome chilblain lupus, retinal vasculopathy and cerebral leukodystrophy (RVCL), systemic sclerosis, myositis, psoriasis, chronic obstructive pulmonary disease (CPD), inflammatory bowel disease (IBD), obesity, insulin resistance, type 2 diabetes (NIDDM), metabolic syndrome, cancer diseases,
Accordingly, the compounds according to the invention or a pharmaceutically acceptable salt thereof are administered for the treatment of cancer, including solid carcinomas, such as, for example, carcinomas (for example of the lungs, pancreas, thyroid, bladder or colon), myeloid diseases (for example myeloid leukaemia) or adenomas (for example villous colon adenoma).
The tumours furthermore include monocytic leukaemia, brain, urogenital, lymphatic system, stomach, laryngeal and lung carcinoma, including lung adenocarcinoma and small-cell lung carcinoma, pancreatic and/or breast carcinoma.
The compounds are furthermore useful in the treatment of immune deficiency induced by HIV-1 (Human Immunodeficiency Virus Type 1).
Cancer-like hyperproliferative diseases are to be regarded as brain cancer, lung cancer, squamous epithelial cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynecological cancer, thyroid cancer, lymphomas, chronic leukaemia and acute leukaemia. In particular, cancer-like cell growth is a disease which represents a target of the present invention. The present invention therefore relates to compounds according to the invention as medicaments and/or medicament active compounds in the treatment and/or prophylaxis of the said diseases and to the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and/or prophylaxis of the said diseases and to a process for the treatment of the said diseases comprising the administration of one or more compounds according to the invention to a patient in need of such an administration.
It can be shown that the compounds according to the invention have an antiproliferative action. The compounds according to the invention are administered to a patient having a hyperproliferative disease, for example to inhibit tumour growth, to reduce inflammation associated with a lymphoproliferative disease, to inhibit transplant rejection or neurological damage due to tissue repair, etc. The present compounds are suitable for prophylactic or therapeutic purposes. As used herein, the term “treatment” is used to refer to both the prevention of diseases and the treatment of pre-existing conditions. The prevention of proliferation/vitality is achieved by administration of the compounds according to the invention prior to the development of overt disease, for example for preventing tumour growth. Alternatively, the compounds are used for the treatment of chronic diseases by stabilising or improving the clinical symptoms of the patient.
The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of a human disease.
The susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by in vitro testing. Typically, a culture of the cell is incubated with a compound according to the invention at various concentrations for a period of time which is sufficient to allow the active agents to induce cell death or to inhibit cell proliferation, cell vitality or migration, usually between about one hour and one week. In vitro testing can be carried out using cultivated cells from a biopsy sample. The amount of cells remaining after the treatment are then determined.
The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient considerably to reduce the undesired cell population in the target tissue, while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.
There are many diseases associated with deregulation of cell proliferation and cell death (apoptosis). The conditions of interest include, but are not limited to, the following. The compounds according to the invention are suitable for the treatment of various conditions where there is proliferation and/or migration of smooth muscle cells and/or inflammatory cells into the intimal layer of a vessel, resulting in restricted blood flow through that vessel, for example in the case of neointimal occlusive lesions. Occlusive graft vascular diseases of interest include atherosclerosis, coronary vascular disease after grafting, vein graft stenosis, perianastomatic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.
In addition, the compounds according to the invention can be used to achieve additive or synergistic effects in certain existing cancer chemotherapies and radiotherapies and/or to restore the efficacy of certain existing cancer chemotherapies and radiotherapies.
The term “method” refers to manners, means, techniques and procedures for accomplishing a given task, including, but not limited to, those manners, means, techniques and procedures which are either known to the person skilled in the art in the chemical, pharmacological, biological, biochemical and medical area or can easily be developed by him from known manners, means, techniques and procedures b.
The term “administration” as used here refers to a method for bringing a compound of the present invention and a target kinase together in such a way that the compound is able to affect the enzyme activity of the kinase either directly, i.e. by interaction with the kinase itself, or indirectly, i.e. by interaction with another molecule on which the catalytic activity of the kinase is dependent. As used here, administration can be carried out either in vitro, i.e. in a test tube, or in vivo, i.e. in cells or tissues of a living organism.
The term “treatment” here encompasses abrogation, substantial inhibition, slowing or reversal of the progress of a disease or disorder, substantial amelioration of the clinical symptoms of a disease or disorder or substantial prevention of the occurrence of clinical symptoms of a disease or disorder.
The term “prevention” here refers to a method for blocking an organism from acquiring a disorder or disease in the first place.
For any desired compound used in this invention, a therapeutically effective amount, also referred to here as a therapeutically effective dose, can be calculated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 or the IC100 as determined in cell cultures. This information can be used to determine useful doses for humans more accurately. Initial dosages can also be calculated from in-vivo data. Using these initial guidelines, an average person skilled in the art could determine an effective dosage for humans.
Moreover, the toxicity and therapeutic efficacy of the compounds described here can be determined by standard pharmaceutical procedures on cell cultures or experimental animals, for example by determining the LD50 and the ED50. The dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD50 and ED50. Compounds which exhibit a high therapeutic index are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a dosage range which is not toxic for human use. The dosage of such compounds is preferably in bloodstream concentration ranges which include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration used. The precise formulation, route of administration and dosage can be selected by the individual physician taking into account the patient's condition (see, for example, Fingl et al., 1975, in: The Pharmacological Basis of Therapeutics, Chapter 1, page 1).
Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to obtain a therapeutic effect. Usual patient dosages for oral administration are in the range from about 50-2000 mg/kg/day, generally from about 100-1000 mg/kg/day, preferably from about 150-700 mg/kg/day and particularly preferably from about 250-500 mg/kg/day.
Therapeutically effective serum levels are preferably achieved by administration of multiple doses per day. In the case of local administration or selective uptake, the effective local concentration of the medicament may not be related to the plasma concentration. The person skilled in the art will be able to optimise therapeutically effective local dosages without undue experimentation.
Preferred diseases or disorders for the prevention, treatment and/or investigation of which the compounds described here may be useful are cell proliferative disorders, in particular cancer, such as, but not limited to, papilloma, blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, skin cancer, liver cancer, bladder cancer, breast cancer, lung cancer, uterine cancer, prostate cancer, testicular carcinoma, colorectal cancer, thyroid cancer, pancreatic cancer, stomach cancer, hepatocellular carcinoma, leukaemia, lymphoma, Hodgkin's disease and Burkitt's disease.